It is known that IL-2 receptor-bearing T-lymphocytes (CD3+, CD25+, CD122+) induce type I psoriasis. The hypothesis addressed in the current proposal is: (1) T-cell mediating psoriasis are MHC class I restricted and belong to the Tc1 subset of effector CD8+ lymphocytes. The following hypotheses regarding the mechanism will also be discussed: (2) CD4+ T cells (or other IL-2 receptor-bearing cells) are pathogenic. (3) Type I psoriasis is a primary disorder of keratinocytes with activation of T cells as a secondary event. (4) Activated Langerhans cells (or other dendritic antigen-presenting cell types) are directly pathogenic. IL-2 receptor-bearing T-lymphocytes (CD3+CD25+CD122+) induce type I psoriasis. T-cells mediating psoriasis are most likely MHC class I restricted and belong to the Tc1 subset of effector CD8+ lymphocytes. The major alternative hypothesis is that other IL-2 receptor-bearing cells, especially CD4+ T-cells, are pathogenic. Less likely alternative hypotheses are 1) that type I psoriasis is a primary disorder of keratinocytes with activation of T cells as a secondary event or 2) that activated Langerhans cells (or other dendritic antigen-presenting cell types) are directly pathogenic. This hypothesis is being tested by the in vivo administration of three novel immune-modulating drugs (which target activation and/or effector phases of immune responses) to patients with psoriasis vulgaris. Two of these agents directly target IL-2 receptors that are up-regulated on activated T-lymphocytes, and the other agent indirectly suppresses IL-2 receptor expression by T-lymphocytes. The agents being studied are DAB389IL2, a rationally engineered fusion toxin which binds selectively to activated T-lymphocytes; rh Interleukin-11, an anti-inflammatory that modulates T-lymphocyte activation, and a humanized monoclonal antibody to CD25, the subunit of the IL-2 receptor that confers high-affinity interaction with IL-2. The major objectives of these studies are, first, to explore the safety and efficacy of novel immune-targeted therapeutic agents in the most common human immune-mediated disease (psoriasis vulgaris) and, secondly, to use these therapeutic agents as specific immune probes to dissect the contribution of different immune mechanisms to disease pathogenesis. Hence, our analysis plan is geared to investigate a broad range of immune pathways that might be affected by each agent. Proposed studies include analysis of (1) Molecules regulating early, mid, and late stages of T-cell activation, including expression of pathways such as CTLA4, Fas, and Fas ligand, believed to terminate immune responses; (2) Type I vs. type II cytokines synthesized by individual T-lymphocytes using new flow cytometry-based techniques (defines some subsets of effector lymphocytes); (3) Differentiation of memory vs. effector populations of CD8+ and CD4+ T-cell subsets using multiple molecular markers such as GMP-17 (TIA-1), CD27, CD28, CD57, CD45 isoforms, and CD29; (4) Trafficking of T-cells into psoriatic skin lesions, including expression of regulatory adhesion molecules such as CLA, CD11a, ICAM-1, CD29, and P/Eselectins; (5) Down-regulation of immune responses as measured by induction of T-cell apoptosis vs. induction of T-cell anergy. Furthermore, "mature" or activated Langerhans cells (as well as other types of dendritic antigen-presenting cells) may provide the stimulus for ongoing T-cell activation in psoriatic skin lesions. Hence, we will also study the effects of specific immune-blockade on the expression of co-stimulatory molecules (CD80, CD86, CD54, and CD40) that are up-regulated on dendritic cells in psoriatic skin lesions.